Voriconazole is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:

1.1 Invasive Aspergillosis

In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and Clinical Pharmacology (12.4)].

1.2 Candidemia in Non-neutropenic Patients and the Following Candida Infections: Disseminated Infections in Skin and Infections in Abdomen, Kidney, Bladder Wall, and Wounds

[See Clinical Studies (14.2) and Clinical Pharmacology (12.4).]

1.3 Esophageal Candidiasis

[See Clinical Studies (14.3) and Clinical Pharmacology (12.4).]

1.4 Serious Fungal Infections Caused by Scedosporium apiospermum (Asexual Form of Pseudallescheria boydii) and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other Therapy

[See Clinical Studies (14.4) and Clinical Pharmacology (12.4).]

Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

2.1 Instructions for Use in All Patients

Voriconazole Tablets should be taken at least one hour before or after a meal.

2.3 Recommended Dosing in Adults

2.4 Dosage Adjustment

If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.

The maintenance dose of voriconazole should be increased when coadministered with phenytoin or efavirenz [see Drug Interactions (7)].

The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C). Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression and clinical response.

Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression and clinical response.

2.7 Use in Patients with Hepatic Impairment

In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.9)].

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].

Voriconazole has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

2.8 Use in Patients with Renal Impairment

The pharmacokinetics of orally administered voriconazole are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

Tablets

Voriconazole 50 mg tablets: White, film-coated, round shaped, debossed with "V above 5" on one side and Plain on the reverse.

Voriconazole 200 mg tablets: White, film-coated, capsule shaped, debossed with "V2" on one side and plain on the reverse.

• Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
• Coadministration of terfenadine, astemizole, cisapride, pimozide or quinidine with voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of Torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [see Drug Interactions (7) andClinical Pharmacology (12.3)] .
• Coadministration of voriconazole with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7) andClinical Pharmacology (12.3)] .
• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg q24h or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with high dose ritonavir (400 mg q12h) is contraindicated because ritonavir (400 mg q12h) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
• Coadministration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .
• Coadministration of voriconazole with St. John's Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration [see Drug Interactions (7) and Clinical Pharmacology (12.3)] .

5.1 Drug Interactions

See Table 6 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 7 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].

5.2 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Warnings and Precautions (5.9) and Adverse Reactions (6.3)].

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies continued use [see Warnings and Precautions (5.9), Dosage and Administration (2.4, 2.7), and Adverse Reactions (6.3)].

5.3 Visual Disturbances

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [see Adverse Reactions (6.2)].

5.4 Embryo-Fetal Toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality. Please refer to section 8.1 (Pregnancy) for additional details.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.

5.5 Galactose Intolerance

Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

5.6 Arrhythmias and QT Prolongation

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as Torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• Congenital or acquired QT-prolongation
• Cardiomyopathy, in particular when heart failure is present
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant medicinal product that is known to prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3) ]

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3)].

5.7 Infusion Related Reactions

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

5.8 Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

5.9 Patients with Hepatic Impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving voriconazole [see Clinical Pharmacology (12.3) and Dosage and Administration (2.7)].

Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

5.10 Patients with Renal Impairment

In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.8)].

5.11 Monitoring of Renal Function

Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

5.12 Monitoring of Pancreatic Function

Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole treatment.

5.13 Dermatological Reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome, have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.

Voriconazole has been associated with photosensitivity skin reaction. Patients, including children, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

5.14 Skeletal Adverse Events

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.4)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Overview

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash and visual disturbances [see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2, 6.3)].

6.2 Clinical Trial Experience in Adults

The data described in Table 2 reflect exposure to voriconazole in 1,655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11 to 90, including 51 patients aged 12 to 18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over 6 months. Table 2 includes all adverse events which were reported at an incidence of ≥ 2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of < 2%.

In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from voriconazole study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 2. Treatment Emergent Adverse Events: Rate ≥ 2% on Voriconazole or Adverse Events of Concern in All Therapeutic Studies Population, Studies 307/602-608 Combined or Study 305. Possibly Related to Therapy or Causality Unknown#

#Study 307/602: invasive aspergillosis; Study 608: candidemia; Study 305: esophageal candidiasis

*Amphotericin B followed by other licensed antifungal therapy

**See Warnings and Precautions (5.3)

6.3 Clinical Laboratory Values

The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1,655) of patients treated with voriconazole. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.

Liver function tests should be evaluated at the start of and during the course of voriconazole therapy. Patients who develop abnormal liver function tests during voriconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole [see Warnings and Precautions (5.2)].

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Tables 3 to 5 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with esophageal candidiasis were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.

Table 3. Protocol 305 – Patients with Esophageal Candidiasis Clinically Significant Laboratory Test Abnormalities

*Without regard to baseline value

n = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

Table 4. Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities

*Without regard to baseline value

**Amphotericin B followed by other licensed antifungal therapy

n = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

LLN = lower limit of normal

Table 5. Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities

*Without regard to baseline value

n = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

LLN = lower limit of normal

6.4 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skeletal: Fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.14)].

Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]

*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects

**Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects

*** Non-Nucleoside Reverse Transcriptase Inhibitors

Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]

* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects

** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects

*** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h)

**** Non-Steroidal Anti-Inflammatory Drug

***** Non-Nucleoside Reverse Transcriptase Inhibitors

8.1 Pregnancy

Risk Summary

Voriconazole can cause fetal harm when administered to a pregnant woman.  There are no availabledata on the use of voriconazole in pregnant women.  In animal reproduction studies, oral, voriconazole was teratogenic in rats and embryotoxic in rabbits.  Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the recommended maintenance dose of 200 mg every 12 hours based on body surface area comparisons).  In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis.  Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. [see Data].  If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.4)]. 

The background risk of major birth defects and miscarriage for the indicated populations is unknown.  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

Data

8.2 Lactation

Risk Summary

No data are available regarding the presence of voriconazole in human milk, the effects of voriconazole on the breastfed infant, or the effects on milk production.  The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for voriconazole and any potential adverse effects on the breastfed child from voriconazole or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Advise females of reproductive potential to use effective contraception during treatment with voriconazole.  The coadministration of voriconazole with the oral contraceptive, Ortho-Novum® (35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect.  Monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

A total of 22 patients aged 12 to 18 years with invasive aspergillosis were included in the therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg q12h.

Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies [see Clinical Pharmacology (12.3)].  A population pharmacokinetic analysis was conducted on pooled data from 35 immunocompromised pediatric patients aged 2 to <12 years old who were included in two pharmacokinetic studies of intravenous voriconazole (single dose and multiple dose).  Twenty-four of these patients received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg.  A comparison of the pediatric and adult population pharmacokinetic data revealed that the predicted average steady state plasma concentrations were similar at the maintenance dose of 4 mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians of 1.19 µg/mL and 1.16 µg/mL in children and adults, respectively).

There have been postmarketing reports of pancreatitis in pediatric patients.

8.5 Geriatric Use

In multiple dose therapeutic trials of voriconazole, 9.2% of patients were  65 years of age and 1.8% of patients were  75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Exposure-Response Relationship For Efficacy and Safety

In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively.  A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy.  However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances [see Adverse Reactions (6)]. 

Cardiac Electrophysiology

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole.  Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period.  The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec.  Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec.  Age was not found to affect the magnitude of increase in QTc.  No subject in any group had an increase in QTc of ≥60 msec from baseline.  No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.  However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown [see Contraindications (4) and Drug Interactions (7)].

12.3 Pharmacokinetics

12.4 Microbiology

12.5 Pharmacogenomics

CYP2C19, significantly involved in the metabolism of voriconazole, exhibits genetic polymorphism.  Approximately 15-20% of Asian populations may be expected to be poor metabolizers.  For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%.  Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCʈ) than their homozygous extensive metabolizer counterparts.  Subjects who are heterozygous extensive metabolizers have, on average 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts [see Clinical Pharmacology (12.3)]

13.1 CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6 or 1.6 times the recommended maintenance dose (RMD) on a mg/m2 basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4 or 1.4 times the RMD on a mg/m2 basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO assay, the mouse micronucleus assay or the DNA repair test (Unscheduled DNA Synthesis assay).

Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD (recommended maintenance dose).

14.1 Invasive Aspergillosis

Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in non-neutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n = 283) or the regimen of amphotericin B followed by fluconazole (n = 139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%) and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 13.

Table 13. Overall Success Rates Sustained From EOT to the Fixed 12 Week Follow-Up Time Point by Baseline PathogenPatients who did not have a 12 week assessment for any reason were considered a treatment failure.

aA few patients had more than one pathogen at baseline.

bPatients who did not have a 12-week assessment for any reason were considered a treatment failure.

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6 or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intra-abdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection and 0 of 1 with cervical lymph node infection.

14.3 Esophageal Candidiasis

The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of esophageal candidiasis was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven esophageal candidiasis. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent to Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against esophageal candidiasis, as presented in Table 14.

Table 14. Success Rates in Patients Treated for Esophageal Candidiasis

aConfidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

bPP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of treatment and had a repeat endoscopy at EOT (end of treatment).

cITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

Microbiologic success rates by Candida species are presented in Table 15.

Table 15. Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study 150-305)

aSome patients had more than one species isolated at baseline

bPatients with endoscopic and/or mycological assessment at end of therapy

14.4 Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks, including one patient with pulmonary, skin and eye infections, one patient with cerebral disease and one patient with skin infection. Ten patients had evidence of cerebral disease and six of these had a successful outcome (one relapse). In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp.- Nine of 21 (43%) patients were successfully treated with voriconazole. Of these nine patients, three had eye infections, one had an eye and blood infection, one had a skin infection, one had a blood infection alone, two had sinus infections and one had disseminated infection (pulmonary, skin, hepatosplenic). Three of these patients (one with disseminated disease, one with an eye infection and one with a blood infection) had Fusarium solani and were complete successes. Two of these patients relapsed, one with a sinus infection and profound neutropenia and one post surgical patient with blood and eye infections.

16.1 How Supplied

16.2 Storage

Voriconazole Tablets should be stored at 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature].

Read the Patient Information that comes with voriconazole before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your condition or treatment.

What is voriconazole?

Voriconazole is a prescription medicine used to treat certain serious fungal infections in your blood and body. These infections are called "aspergillosis," "esophageal candidiasis," "Scedosporium," "Fusarium" and "candidemia".

It is not known if voriconazole is safe and effective in children younger than 12 years old.

Who should not take voriconazole?

Do not take voriconazole if you:

• are allergic to voriconazole or any of the ingredients in voriconazole . See the end of this leaflet for a complete list of ingredients in voriconazole.
• are taking any of the following medicines:
  • cisapride (Propulsid®)
  • pimozide (Orap®)
  • quinidine (like Quinaglute®)
  • sirolimus (Rapamune®)
  • rifampin (Rifadin®)
  • carbamazepine (Tegretol®)
  • long-acting barbiturates like phenobarbital (Luminal®)
  • efavirenz (Sustiva®)
  • ritonavir (Norvir®)
  • rifabutin (Mycobutin®)
  • ergotamine, dihydroergotamine (ergot alkaloids)
  • St. John's Wort (herbal supplement)

Ask your healthcare provider or pharmacist if you are not sure if you are taking any of the medicines listed above.

Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

What should I tell my healthcare provider before taking voriconazole?

Before you take voriconazole, tell your healthcare provider if you:

• have or ever had heart disease or an abnormal heart rate or rhythm. Your healthcare provider may order a test to check your heart (EKG) before starting voriconazole.
• have liver or kidney problems. Your healthcare provider may do blood tests to make sure you can take voriconazole.
• have trouble digesting dairy products or regular table sugar. Voriconazole tablets contain lactose.
• are pregnant or plan to become pregnant. Voriconazole can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Women who can become pregnant should use effective birth control while taking voriconazole.
• are breast-feeding or plan to breast-feed. It is not known if voriconazole passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take voriconazole.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Voriconazole may affect the way other medicines work, and other medicines may affect how voriconazole works.

Know what medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take voriconazole?

• Voriconazole may be prescribed to you as :
  • Voriconazole tablets
• Take voriconazole tablets exactly as your healthcare provider tells you to.
• Take voriconazole tablets at least one hour before or at least one hour after meals.
• If you take too much voriconazole, call your healthcare provider or go to the nearest hospital emergency room.

What should I avoid while taking voriconazole?

• You should not drive at night while taking voriconazole. Voriconazole can cause changes in your vision such as blurring or sensitivity to light.
• Do not drive or operate machinery, or do other dangerous activities until you know how voriconazole affects you.
• Avoid direct sunlight. Voriconazole can make your skin sensitive to the sun and the light from sunlamps and tanning beds. You could get a severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your healthcare provider if you get sunburn.

What are possible side effects of voriconazole?

Voriconazole may cause serious side effects including:

• liver problems. Symptoms of liver problems may include:
  • itchy skin
  • yellowing of your eyes
  • feeling very tired
  • flu-like symptoms
  • nausea or vomiting
• vision changes. Symptoms of vision changes may include:
  • blurred vision
  • changes in the way you see colors
  • sensitivity to light (photophobia)
• serious heart problems. Voriconazole may cause changes in your heart rate or rhythm, including your heart stopping (cardiac arrest).
• allergic reactions. Symptoms of an allergic reaction may include:
  • fever
  • sweating
  • feels like your heart is beating fast (tachycardia)
  • chest tightness
  • trouble breathing
  • feel faint
  • nausea
  • itching
  • skin rash
• kidney problems . Voriconazole may cause new or worse problems with kidney function, including kidney failure. Your healthcare provider should check your kidney function while you are taking voriconazole. Your healthcare provider will decide if you can keep taking voriconazole.
• serious skin reactions . Symptoms of serious skin reactions may include:
  • rash or hives
  • mouth sores
  • blistering or peeling of your skin
  • trouble swallowing or breathing

Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.

The most common side effects of voriconazole include:

• vision changes
• rash
• vomiting
• nausea
• headache
• fast heart beat (tachycardia)
• hallucinations (seeing or hearing things that are not there)
• abnormal liver function tests

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of voriconazole. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store voriconazole?

• Store voriconazole tablets at room temperature, 59o to 86o F (15 to 30C). Do not refrigerate or freeze.
• Keep voriconazole tablets in a tightly closed container.
• Safely throw away medicine that is out of date or no longer needed.
• Keep voriconazole, as well as all other medicines, out of the reach of children.

General information about the safe and effective use of voriconazole

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use voriconazole for a condition for which it was not prescribed. Do not give voriconazole to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about voriconazole. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about voriconazole that is written for health professionals.

For more information, call Novel Laboratories, Inc. at 866-403-7592.

What are the ingredients of voriconazole?

Active ingredient: voriconazole

Inactive ingredients:

lactose monohydrate, pregelatinized starch (maize starch), croscarmellose sodium, povidone, magnesium stearate, and a coating containing  hypromellose (HPMC 2910), titanium dioxide, lactose monohydrate, and triacetin.

This Patient Information has been approved by the U.S. Food and Drug Administration.

The brands listed are trademarks of their respective owners.

Manufactured by:

Novel Laboratories, Inc.

Somerset, NJ 08873

PI0890000101

Iss. 01/2016